This grant application is a competitive renewal of an ongoing research effort focused on the development of new polymers for medical applications. Under previous NIH support, a new family of degradable, tyrosine-derived polycarbonates were investigated. One of these materials, poly(DTE carbonate), supports the attachment and growth of cells, bonds to bone without an intervening fibrous tissue layer, and is highly osteoconductive in vivo. These observations represent the foundation for the continuation of this research project. It is now proposed to address the materials need in the emerging field of tissue reconstruction/engineering, with special emphasis on the development of degradable, polymeric scaffolds for use in bone. The guiding hypothesis is that optimum cell proliferation and differentiation within a polymeric scaffold requires the independent optimization of both materials-related and pore architecture-related design parameters. To address this hypothesis, this project is focused on (l) the design of a series of new polymers that can be used to elucidate the mechanisms by which material properties affect the cellular response; (2) the improvement of phase separation/salt leaching techniques for the fabrication of scaffolds with reproducible and systematic changes in their pore architecture; (3) a detailed investigation of the materials-dependent and pore architecture- dependent effects on the cellular response in vitro and in vivo; and (4) the application of the knowledge gained to design an optimized scaffold to serve as a bone graft to be tested in a clinically relevant spine fusion model. Most laboratories working on polymeric scaffolds use simple polyesters, e.g., PLA, PGA. In contrast, this research effort emphasizes the systematic side-by-side comparison of poly(DTE carbonate), PLA, and a series of new copolymers of DTE and lactic acid. Within this framework, the mechanisms will be elucidated for the different bone response observed for poly(DTE carbonate) as compared to poly(lactic acid) and new techniques will be introduced to assess more accurately cell proliferation and differentiation within a polymeric scaffold as function of the material properties and pore architecture. It is expected that this research project will contribute to a better understanding of the basic scaffold design parameters leading to an optimized cellular response for bone regeneration.